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Objective The objective of this study was to identify the age of diagnosis for children with one of three neurogenetic conditions resulting from changes in chromosome 15 (Angelman syndrome [AS], Prader-Willi syndrome [PWS], and duplication 15q syndrome [Dup15q]). Methods Data about the diagnostic process for each condition were contributed by the advocacy organizations. Median and interquartile ranges were calculated for each condition by molecular subtype and year. Comparison tests were run to explore group differences. Results The median age of diagnosis was 1.8 years for both AS and Dup15q. PWS was diagnosed significantly younger at a median age of 1 month. Deletion subtypes for both PWS and AS were diagnosed earlier than nondeletion subtypes, and children with isodicentric duplications in Dup15q were diagnosed earlier than those with interstitial duplications. Conclusion Understanding variability in the age of diagnosis for chromosome 15 disorders is an important step in reducing the diagnostic odyssey and improving access to interventions for these populations. Results from this study provide a baseline by which to evaluate efforts to reduce the age of diagnosis for individuals with these conditions.

Rapid advances in the screening, diagnosis, and treatment of genetic disorders have increased the number of conditions that can be detected through universal newborn screening (NBS). However, the addition of conditions to the Recommended Uniform Screening Panel (RUSP) and the implementation of nationwide screening has been a slow process taking several years to accomplish for individual conditions. Here, we describe web-based tools and resources developed and implemented by the newborn screening translational research network (NBSTRN) to advance newborn screening research and support NBS stakeholders worldwide. The NBSTRN’s tools include the Longitudinal Pediatric Data Resource (LPDR), the NBS Condition Resource (NBS-CR), the NBS Virtual Repository (NBS-VR), and the Ethical, Legal, and Social Issues (ELSI) Advantage. Research programs, including the Inborn Errors of Metabolism Information System (IBEM-IS), BabySeq, EarlyCheck, and Family Narratives Use Cases, have utilized NBSTRN’s tools and, in turn, contributed research data to further expand and refine these resources. Additionally, we discuss ongoing tool development to facilitate the expansion of genetic disease screening in increasingly diverse populations. In conclusion, NBSTRN’s tools and resources provide a trusted platform to enable NBS stakeholders to advance NBS research and improve clinical care for patients and their families.

Chiari Type I Malformation (CMI) is characterized by displacement of the cerebellar tonsils below the base of the skull, resulting in significant neurologic morbidity. Although multiple lines of evidence support a genetic contribution to disease, no genes have been identified. We therefore conducted the largest whole genome linkage screen to date using 367 individuals from 66 families with at least two individuals presenting with nonsyndromic CMI with or without syringomyelia. Initial findings across all 66 families showed minimal evidence for linkage due to suspected genetic heterogeneity. In order to improve power to localize susceptibility genes, stratified linkage analyses were performed using clinical criteria to differentiate families based on etiologic factors. Families were stratified on the presence or absence of clinical features associated with connective tissue disorders (CTDs) since CMI and CTDs frequently co-occur and it has been proposed that CMI patients with CTDs represent a distinct class of patients with a different underlying disease mechanism. Stratified linkage analyses resulted in a marked increase in evidence of linkage to multiple genomic regions consistent with reduced genetic heterogeneity. Of particular interest were two regions (Chr8, Max LOD = 3.04; Chr12, Max LOD = 2.09) identified within the subset of \"CTD-negative\" families, both of which harbor growth differentiation factors (GDF6, GDF3) implicated in the development of Klippel-Feil syndrome (KFS). Interestingly, roughly 3-5% of CMI patients are diagnosed with KFS. In order to investigate the possibility that CMI and KFS are allelic, GDF3 and GDF6 were sequenced leading to the identification of a previously known KFS missense mutation and potential regulatory variants in GDF6. This study has demonstrated the value of reducing genetic heterogeneity by clinical stratification implicating several convincing biological candidates and further supporting the hypothesis that multiple, distinct mechanisms are responsible for CMI.

Objectives To review the referral and clinical characteristics of adult patients diagnosed with lysosomal storage diseases (LSD) through the Undiagnosed Diseases Network (UDN). Methods Retrospective review of both application and evaluation records for adults admitted to the UDN with a final diagnosis of a lysosomal storage disease. Results Ten patients were identified. Final diagnoses included late onset Tay Sachs, attenuated MPS I, MPS IIIA, MPS IIIB, and MPS IIIC. Most patients presented with neurocognitive changes. Prior to referral, all patients had been evaluated by neurology, four patients underwent phenotype specific panel testing that did not include the causative gene, and four patients had non‐diagnostic clinical exome sequencing. Conclusions LSDs figure highly in the differential diagnosis of neurometabolic disorders in pediatric onset progressive diseases. In adults, their subtle initial presentations overlap with symptoms of more common disorders and less practitioner awareness may lead to prolonged diagnostic challenges. We present 10 adults referred to the Undiagnosed Disease Network with a final diagnosis of a Lysosomal Storage Disease. Review of referral patterns and initial evaluation highlight an overrepresentation of neuropsychiatric presentations and limitations to standard of care testing.

Background Resources within the Undiagnosed Diseases Network (UDN), such as genome sequencing (GS) and model organisms aid in diagnosis and identification of new disease genes, but are currently difficult to access by clinical providers. While these resources do contribute to diagnoses in many cases, they are not always necessary to reach diagnostic resolution. The UDN experience has been that participants can also receive diagnoses through the thoughtful and customized application of approaches and resources that are readily available in clinical settings. Methods The UDN Genetic Counseling and Testing Working Group collected case vignettes that illustrated how clinically available methods resulted in diagnoses. The case vignettes were classified into three themes; phenotypic considerations, selection of genetic testing, and evaluating exome/GS variants and data. Results We present 12 participants that illustrate how clinical practices such as phenotype‐driven genomic investigations, consideration of variable expressivity, selecting the relevant tissue of interest for testing, utilizing updated testing platforms, and recognition of alternate transcript nomenclature resulted in diagnoses. Conclusion These examples demonstrate that when a diagnosis is elusive, an iterative patient‐specific approach utilizing assessment options available to clinical providers may solve a portion of cases. However, this does require increased provider time commitment, a particular challenge in the current practice of genomics.

Diagnosing monogenic diseases facilitates optimal care, but can involve the manual evaluation of hundreds of genetic variants per case. Computational tools like Phrank expedite this process by ranking all candidate genes by their ability to explain the patient’s phenotypes. To use these tools, busy clinicians must manually encode patient phenotypes from lengthy clinical notes. With 100 million human genomes estimated to be sequenced by 2025, a fast alternative to manual phenotype extraction from clinical notes will become necessary. We introduce ClinPhen, a fast, high-accuracy tool that automatically converts clinical notes into a prioritized list of patient phenotypes using Human Phenotype Ontology (HPO) terms. ClinPhen shows superior accuracy and 20× speedup over existing phenotype extractors, and its novel phenotype prioritization scheme improves the performance of gene-ranking tools. While a dedicated clinician can process 200 patient records in a 40-hour workweek, ClinPhen does the same in 10minutes. Compared with manual phenotype extraction, ClinPhen saves an additional 3–5hours per Mendelian disease diagnosis. Providers can now add ClinPhen’s output to each summary note attached to a filled testing laboratory request form. ClinPhen makes a substantial contribution to improvements in efficiency critically needed to meet the surging demand for clinical diagnostic sequencing.

Exercise hyperemia and functional capacity are reduced with advancing age and contribute to increased cardiovascular disease/event risk. We hypothesized that 8 weeks of home-based leg heat therapy would improve exercise hyperemia secondary to enhanced vascular conductance during dynamic plantar flexion exercise in primary aging. Additionally, we hypothesized that this intervention would increase functional capacity, as assessed by 6-minute walk distance and Short Physical Performance Battery performance scores. We found that there was no change in exercise hyperemia or functional capacity in older adults after 8 weeks of home-based leg heat therapy. Our findings indicate that home-based leg heat therapy with the prescribed intensity and duration is not an appropriate intervention to improve these outcomes in older adults.

Located in the critical 1p36 microdeletion region, the chromodomain helicase DNA-binding protein 5 (CHD5) gene encodes a subunit of the nucleosome remodeling and deacetylation (NuRD) complex required for neuronal development. Pathogenic variants in six of nine chromodomain (CHD) genes cause autosomal dominant neurodevelopmental disorders, while CHD5-related disorders are still unknown. Thanks to GeneMatcher and international collaborations, we assembled a cohort of 16 unrelated individuals harboring heterozygous CHD5 variants, all identified by exome sequencing. Twelve patients had de novo CHD5 variants, including ten missense and two splice site variants. Three familial cases had nonsense or missense variants segregating with speech delay, learning disabilities, and/or craniosynostosis. One patient carried a frameshift variant of unknown inheritance due to unavailability of the father. The most common clinical features included language deficits (81%), behavioral symptoms (69%), intellectual disability (64%), epilepsy (62%), and motor delay (56%). Epilepsy types were variable, with West syndrome observed in three patients, generalized tonic–clonic seizures in two, and other subtypes observed in one individual each. Our findings suggest that, in line with other CHD-related disorders, heterozygous CHD5 variants are associated with a variable neurodevelopmental syndrome that includes intellectual disability with speech delay, epilepsy, and behavioral problems as main features.

Little is known about the psychosocial profiles of parents who have a child with an undiagnosed chronic illness. The National Institutes of Health Undiagnosed Diseases Network (UDN) evaluates individuals with intractable medical findings, with the objective of discovering the underlying diagnosis. We report on the psychosocial profiles of 50 parents whose children were accepted to one of the network’s clinical sites. Parents completed questionnaires assessing anxiety, depression, coping self-efficacy, and health care empowerment at the beginning of their child’s UDN clinical evaluation. Parents of undiagnosed children had high rates of anxiety and depression (~ 40%), which were significantly inversely correlated with coping self-efficacy, but not with health care empowerment. Coping self-efficacy, depressive, and anxiety symptoms were better in parents with older children and with longer duration of illness. Gender differences were identified, with mothers reporting greater health care engagement than fathers. Overall, our findings suggest that parents of children with undiagnosed diseases maintain positive coping self-efficacy and remain actively engaged in health care and to a lesser degree tolerance for uncertainty, but these come with a high emotional cost to the parents. As the parents’ psychological needs may not be obvious, these should be ascertained and the requisite support provided.

Genetic counselors may meet with expectant parents to facilitate decision making following prenatal diagnosis of anencephaly. Factors that contribute to pregnancy management decisions and the perceived helpfulness of genetic counseling in this patient population are not fully understood. Women and their male partners who previously received a prenatal diagnosis of anencephaly completed mixed-methods questionnaires to assess decision-making factors and the impact of genetic counseling. Lethality of the anomaly and religious and ethical views factored most into pregnancy management decisions. Over half of participants met with a genetic counselor; however nearly one-third did not find the meeting helpful. Genetic counselors may need to prioritize psychosocial support and provision of resources to meet the needs of expectant couples receiving a prenatal diagnosis of anencephaly.